There is no satisfactory treatment available to prevent, delay or reverse the geriatric learning and memory dysfunction which is the hallmark of age-related dementia. The proposed research will evaluate whether the Senescence Accelerated Mouse (SAM P/8) is a useful model to study age-related changes in learning and memory. The SAM P/8 strain has a 37% increase in the rate of aging beyond maturation but develops learning dysfunction at twice the rate of mice with normal life spans such as its geneticcounteer part the SAM R/1 or the C57BL/6Nnia strains. Preliminary data indicates that CAT activity shows an age-related decrease cholinomimetic administration will only enhance retention in older SAM mice if the dose is increased above that needed to enhance retention in age-matched controls having a normal life span. We will examine the ability of the SAM P/8 mice to learn and remember aversive and appetitive tasks of varying degrees of complexity. The ability of the SAM P/8 mice to learn and remember will be compared to its genetic control, SAM R/1, which does not show accelerated aging and the C57BL/6Nnia mouse strain which is the most widely used strain of mice in aging studies. SAM P/8 mice show an age dependent increase in granules in the hippocampus which react positively to period acid Schiff's reaction (PAS). These PAS-positive granules appear at a much early age in SAM P/8 mice than in the SAM R/1 or C57BL strains. We will examine more closely the age-related increase in PAS-positive staining granules in the hippocampus of SAM P/8 mice to learning and memory dysfunction and changes in hippocampus neurotransmitter activity. We will relate the alterations in learning and memory dysfunction to changes in pre- and post-synaptic markers for four neurotransmitter systems which are particularly important for memory processing in the hippocampus (i.e., cholinergic, GABAergic, glutaminergic and noradrenergic). We will examine the ability of pharmacological manipulations of these neurotransmitters systems to alleviate memory dysfunction may be the cause of an age-related impairment of learning and memory in SAM P/8 mice, studies of the other major transmitters of the hippocampus known to be involved in memory processing is needed to determine whether a general decline in neurotransmitter function occurs with age or whether it is specific to the cholinergic system. These experiments should allow us to determine which neurotransmitter(s) is responsible for the learning and memory dysfunction in SAM P/8 mice.